In spite of important advances in cardiology over the past couple of decades, pharmacologic treatment of cardiac arrhythmias, espiecally life threatening ventricular arrhythmias, remains largely empiric. The reason stems from a fundamental lack of understanding of the mechanisms that give rise to cardiac rhythm disturbances, incomplete understanding of the mechanisms by which antiarrhythmic drugs act to suppress and in some cases aggravate arrhythmias, and a lack of criteria by which to base a differential diagnosis of specific arrhythmia mechanisms. The proposed study addresses all of these areas through a multilevel approach involving work with dissociated myocytes, syncytial tissues, intact hearts, mathematical models and clinical ECG analyses. We will focus on two classes of arrhythmia mechanisms, namely reentry (reflection) and early afterdepolarization-induced triggered activity. Utilizing biologic models of these arrhythmias, we will describe the behavioral characteristics of the preparations and assess in depth the cellular and membrane electrophysiologic basis for the phenomena as well as their modulation by drugs. Mathematical models, both empiric and theoretical (Hodgkin-Huxley type), will be employed to facilitate comparison of the experimental findings with the clinical observations and to provide future experimental direction. Clinical correlative data will be sought with the aid of clinical colleagues worldwide and diagnostic criteria will be carefully formulated based on the experimental findings. The ultimate goal of the study is to provide information that will lead to a more definitive and less empiric approach in the pharmacologic and medical management of cardiac rhythm disturbances.